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Shear-Mediated Platelet Activation Enhances Thrombotic Complications in Patients With LVADs and Is Reversed After Heart Transplantation

Consolo, Filippo*; Sferrazza, Giulia; Motolone, Giulia; Pieri, Marina; De Bonis, Michele; Zangrillo, Alberto*,†; Redaelli, Alberto§; Slepian, Marvin J.; Pappalardo, Federico*,†

doi: 10.1097/MAT.0000000000000842
Case Reports

We present a time-series analysis of shear-mediated platelet activation (SMPA) in a patient supported by a Left Ventricular Assist Device (LVAD) who developed recurrent thromboembolic events over the course of support. The patient showed marked alterations of SMPA as quantified via the Platelet Activity State (PAS) assay. At the time of a first pump thrombosis, PAS was equal to 16.2 ± 2.1%, indicating a significant level of SMPA. A moderate decrease of PAS was observed 30 days after pump exchange (PAS = 9.5 ± 1.0%). A sudden PAS increase was recorded after 60 days (PAS = 60.5 ± 4.3%), and an ischemic stroke with hemorrhagic transformation was subsequently diagnosed at 120 days after pump exchange (PAS = 86.9 ± 7.5%); high PAS values did not recover over time likely because of sustained platelet activation from the inflammatory milieu caused by a driveline infection occurred at 240 days of support (PAS = 84.4 ± 7.3%). PAS values were completely reversed after heart transplantation (PAS = 0.6 ± 0.1%), demonstrating resolution of SMPA. This study provides further insight into our understanding of the pathogenesis of LVAD thrombosis, addressing SMPA as a relevant key factor associated with thrombotic complications. With the PAS assay, we have identified a reliable biomarker to promote tailored pharmacological therapy for the prevention of thromboembolic events in patients with LVADs.

From *Università Vita Salute San Raffaele, Milano, Italy

Department of Anesthesia and Cardiothoracic Intensive Care, San Raffaele Scientific Institute, Milano, Italy

Department of Cardiac Surgery, San Raffaele Scientific Institute, Milano, Italy

§Department of Electronics, Information and Bioengineering. Politecnico di Milano, Milano, Italy

Department of Medicine and Biomedical Engineering, Sarver Heart Center, The University of Arizona, Arizona, USA.

Submitted for consideration December 2017; accepted for publication in revised form May 2018.

Disclosure: The authors have no conflicts of interest to report.

This study was financially supported by Fondazione Cariplo grants 2011–2241 and 2015–1044 and by Fondazione Cariplo-Regione Lombarida grant 2016-0901.

Clinical Trial Registration:; Identifier: NCT03255928.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML and PDF versions of this article on the journal’s Web site (

Correspondence: Filippo Consolo, PhD, Università Vita Salute San Raffaele, Via Olgettina 58 - 20132, Milano, Italy. Email:

Left Ventricular Assist Devices (LVADs) are rapidly emerging as the mainstay of therapy of patients with advanced systolic heart failure refractory to medical management.1 Latest generation continuous-flow LVADs while demonstrating increase in patient survival and overall outcome improvement unfortunately remains hampered by pump thrombosis and thromboembolic complications.1–4

Shear-mediated platelet activation (SMPA), defined as platelet prothrombotic activity resulting from accumulation of platelet damage associated with exposure to elevated shear stress over recirculation through the pump, has been proposed to drive thromboembolic events in patients with LVADs.5 However, to date, a clinically reliable diagnostic test of the platelet response to shear stress has been lacking, limiting our understanding of this phenomenon and the identification of effective preventive pharmacological therapeutic strategies.

Recently, we have introduced the modified prothrombinase Platelet Activity State (PAS) assay as a novel diagnostic tool of prothrombotic platelet function in the setting of LVAD therapy.6,7 The PAS assay is performed on isolated gel-filtered platelets, allowing selective focused analysis on platelet thrombin generation.7 The PAS assay utilizes as substrate acetylated prothrombin, which upon exposure to shear damaged, activated platelet membranes, is converted to thrombin, which is measured as the marker of activation.7 Thrombin generated by conversion of acetylated prothrombin does not further activate platelets in a feedback loop nor convert fibrinogen to fibrin8: this represents the distinctive feature of the PAS assay, allowing assessment of thrombin generation as a clear indicator of the level of SMPA, associated prothrombotic function, and patients’ thrombotic risk. In previous studies, we have shown that elevated PAS values correlate with LVAD thrombosis and thromboembolic complications.6,7 Here, we present a complete time-series analysis of PAS values in a patient who developed recurrent thromboembolic events over the course of LVAD support, further exploring the issue of SMPA as a relevant key factor driving LVAD thrombotic complications.

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Case Report

A 52 year-old male patient (body surface area: 1.75 m2) underwent emergent implantation of HeartMate II LVAD (Thoratec Corporation, Pleasanton, CA) after venoarterial extracorporeal membrane oxygenation support because of acute cardiogenic shock and cardiac arrest in the setting of an acute myocardial infarction (INTERMACS 1). The intention to treat was bridge to candidacy. After in-hospital stabilization and uneventful recovery, the patient was discharged to the rehabilitation facility on warfarin (international normalized ratio [INR]: 2–2.5) and aspirin 100 mg/day. However, pump thrombosis occurred 1 month later, and the patient was readmitted to the intensive care unit with acute heart failure. The PAS assay, measured 24 hours after the event occurrence was equal to 16.2 ± 2.1% (t1, Table 1), indicating a significant level of SMPA (Figure 1; experimental protocol of PAS assay is available online [see Supplemental Information, Supplemental Digital Content,]). Indeed, according to PAS cut-off values defined in our previous work,7 median PAS value associated with a thrombotic event is equal to 6.67% (5.59%–11.98%). The patient required pump exchange and was re-implanted with the HeartMate II LVAD. After another uneventful postoperative course, the patient was managed with the same anticoagulation/antiplatelet regimen. PAS values were measured at 30 and 60 days after pump exchange to evaluate potential recovery of SMPA. A moderate decrease in PAS values was observed at 30 days of support after the patient’s reoperation (t2Table 1; PAS = 9.5 ± 1.0%; Figure 1); however, at 60 days after pump exchange, a sudden increase in PAS values was recorded (t3Table 1; PAS = 60.5 ± 4.3%; Figure 1), and at 120 days, a new thromboembolic event, namely ischemic stroke with hemorrhagic transformation was detected (t4: PAS = 86.9 ± 7.5%; Figure 1). After this event, PAS values did not recover over time, which was suspected to be caused by the inflammatory milieu of a driveline infection occurred at 240 days after pump exchange that contributed to sustain an altered platelet activation level (t5: PAS = 84.4 ± 7.3%; Figure 1).

Figure 1

Figure 1

Because of recurrent complications associated with the LVAD support, the patient was listed for urgent heart transplantation (HT). The patient was successfully transplanted after 465 days of LVAD support. After HT, the antithrombotic therapy was reduced to aspirin alone (100 mg/day). PAS was measured 240 days after HT and was noted to be 141-fold lower than prior values measured while on LVAD support (t6: PAS = 0.6 ± 0.1%; Figure 1). Notably, this value was comparable to that reported for healthy volunteers (0.48%; 0.42%–1.01%).7

In addition to PAS values, laboratory and coagulation parameters were recorded at each time point (Table 1).

Table 1

Table 1

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This clinical report is the first to track thrombotic complications of an LVAD-implanted patient utilizing the PAS assay as a means of identifying the dynamics of alteration of shear-mediated platelet activation over time. Additionally, this study further emphasizes the significant role of LVAD-related SMPA in driving the development of thrombotic complications and the value of HT as a means of ultimately reducing platelet prothrombotic activity.

The presented case demonstrated altered levels of SMPA during the entire period of LVAD support, as measured via the PAS assay, suggesting severe platelet sensitization to LVAD-mediated shear stress, which, importantly, was not reduced or reversed by antithrombotic therapy. Continuous-flow conditions and the high rotational speed of the impeller (average rotational speed = 8800 ± 200 rpm) exposed platelets to supraphysiologic levels of shear stress, resulting in progressive accumulation of shear-mediated platelet damage, as evidenced by an increase in PAS values over time.

Consistent with PAS data, pump thrombosis and late neurologic events are likely primarily attributed to the platelet response to shear stress exerted by the pump, i.e., SMPA. Alternatively, we cannot exclude that physiologic activation of the coagulation cascade in response to hemorrhage that followed the ischemic stroke recorded at t4 might have contributed to sustained elevated PAS values. In addition, abnormal activation over time may have been exacerbated by the inflammatory milieu associated with the driveline infection that occurred at t5.

Interestingly, according to data previously reported by Valerio et al.,6 this study shows that platelets are slow to recover to a physiologic quiescent activity profile after pump exchange in the setting of pump thrombosis. This suggests that continuing monitoring SMPA after pump exchange would be useful to prevent adverse event recurrence. Conversely, HT—which fully removes LVAD-mediated shear stress with restoration of a normal hemodynamic environment—allowed complete reversal of platelet prothrombotic activity, with a return to normal physiologic function. Specifically, SMPA decreased more than 99% compared with prior values measured while on LVAD support.

The results of this study further corroborate our previous study, which analyzed the mechanistic effect of LVAD-related shear stress on platelet function. In the study by Consolo et al.,7 the utility of monitoring SMPA during the preoperative, early postimplant, and long-term follow-up stages was reported. Specifically, systematic analysis of the PAS assay allowed identification of 1) PAS cut-off values that correlate with clinically overt thromboembolic events, 2) SMPA as a preoperative risk factor to the development of thromboembolic complications, and 3) the platelet response to the differing hemodynamic environment characteristics of pumps commercially available, i.e., HeartMate II, HeartMate 3, and HeartWare HVAD).7 With this study, we provide a more fundamental understanding of the pathogenesis of LVAD thromboembolic events as we have linked the dynamics of the mechanobiologic responsiveness of circulating platelets to the LVAD hemodynamic environment and the development of thrombotic complications. Here, we provide first evidence of the predictive capability of the PAS assay as to the occurrence of thromboembolic events and of the potential utility of PAS to prevent these complications. Indeed, elevation in PAS values recorded between t2 and t3 might have been prognostic of the neurologic event that occurred at t4 (Figure 1). On the other hand, we are aware that further studies on a larger cohort of patients will be needed to validate these preliminary results.

Prospectively, the PAS assay has the potential for further validation as a clinically relevant diagnostic test of shear-mediated platelet prothrombotic activity. Having a simple and reliable test would facilitate the identification of individuals who respond poorly to antithrombotic therapy and guide the definition of improved patient-specific antithrombotic regimens. Integration of PAS with standard INR analysis might afford more comprehensive evaluation of patients’ hemostatic system and overall thrombotic risk. Finally, analysis of SMPA via PAS might also drive the promotion of technologic improvement of LVAD design.

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1. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015.34:1495–504.
2. Mehra MR, Naka Y, Uriel N, et al; MOMENTUM 3 Investigators: A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med 2017.376:440–450.
3. Najjar SS, Slaughter MS, Pagani FD, et al; HVAD Bridge to Transplant ADVANCE Trial Investigators: An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial. J Heart Lung Transplant 2014.33: 23–34.
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6. Valerio L, Consolo F, Bluestein D, et al. Shear-mediated platelet activation in patients implanted with continuous flow LVADs: A preliminary study utilizing the platelet activity state (PAS) assay. Conf Proc IEEE Eng Med Biol Soc 2015.2015: 1255–1258.
7. Consolo F, Sferrazza G, Motolone G, et al. Platelet activation is a pre-operative risk factor to the development of thromboembolic complications in patients with continuous flow left ventricular assist device. Eur J Heart Fail 2018.20: 792–800.
8. Jesty J, Bluestein D. Acetylated prothrombin as a substrate in the measurement of the procoagulant activity of platelets: Elimination of the feedback activation of platelets by thrombin. Anal Biochem 1999.272: 64–70.

left ventricular assist device; shear-mediated platelet activation; thrombosis; Platelet Activity State assay; heart transplant

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